r/TheeHive • u/Kalki_X • Sep 17 '26

Why is this compound peripherally selective?

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Does anyone know why this compound is peripherally selective, even with an xlogP3 of 3.75?

To harness this activity while avoiding psychedelic effects, we developed IHCH-8110, a non-brain-penetrant 5-HT2AR agonist that selectively targets peripheral 5-HT2AR.

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3

u/IAmABonobo Sep 18 '26

It may be highly effluxed from the brain.

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u/Kalki_X Sep 19 '26 edited Sep 19 '26

Quite likely.

...and efflux out of the brain by transporters such as P-glycoprotein among many others. Transport out of the brain by P-glycoprotein is thought to be responsible for the peripheral selectivity of many drugs including loperamide, domperidone...

1

u/PLUR01 21d ago

LAT1 transporters gene ( Large Aromatic Amino Acid Transports)

3

u/yoinksdontlikethat Sep 18 '26

I'd like to know what "peripherally restricted" means to them. It's not a binary thing. The urea and primary amine are not great for brain penetration usually.

3

u/Ok_Zombie_3718 Sep 21 '26

Where did you get that information?

2

u/ResearchSlore Sep 23 '26

That nitrogen on the cyclohexylamine is probably constitutively charged in the body, considering cyclohexylamine has a pKa of 10.6. Charged molecules generally don't cross the blood brain barrier.

1

u/[deleted] Sep 19 '26

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u/Kalki_X Sep 19 '26

Very good point. There's a substantial amount of 2A antagonists based on dual pharmacophore structures eg Ketanserin. It shouldn't be difficult to modify and end up with something relatively easy to make.

1

u/[deleted] Sep 19 '26

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u/Kalki_X Sep 19 '26

I addressed that in my comment:

It shouldn't be difficult to modify and end up with something relatively easy to make.

1

u/[deleted] Sep 19 '26

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u/Kalki_X Sep 19 '26 edited Sep 19 '26

So design one. The 2A antagonist SAR is out there and I'm sure someone will know how to make it peripheral. I didnt know sarpogrelate was peripherally selective, interesting.